DESCRIPTION: The ultimate goal of our research efforts is to develop an inducible switch that could be used to treat diseases of the eye, specifically age-related macular degeneration. This research proposal is to translate our experience with regard to transcriptional regulation and develop a regulatory system for combating both inherited and acquired diseases of the eye. Here, we describe a new system to regulate transgene expression based upon the switch that regulates the lac operon. The specific goal of this proposal is to create and quantitatively evaluate an inducible transgene delivery regulatory system to for treating eye diseases. This proposal is a collaboration between two established investigators, Drs. Lewis and Bennett. The Lewis lab has studied inducible systems, focusing particularly on the operon that regulates lactose metabolism in bacteria. They determined the three-dimensional structure of the repressor, bound to operator and inducers [2], have established the allosteric mechanism of this inducible switch [3], and have evolved the repressor and its operator to create an optimal switch[4]. The Bennett lab has focused on understanding the molecular basis of vision and developing rational approaches for treating monogenic diseases of the eye. Using gene therapy, they successfully restored vision in patients suffering from Leber's congenital amaurosis [5, 6]. We are now in a unique position to combine our expertise and translate what we have discovered about gene regulation and gene therapy to develop the next generation of inducible switches for treating a variety of visual deficits. The successful completion of this research will be an inducible switch for regulating therapeutic genes and treating a variety of retinal dystrophies including age-related macular degeneration.